The present invention relates to carbocyclic nucleosides and the pharmaceutically acceptable salts thereof, processes for the preparation of such compounds, intermediates used in the preparation of such compounds, pharmaceutical compositions comprising such compounds, and the uses of such compounds in treating inflammatory skin diseases, including, but not limited to, psoriasis, eczema and seborrhiasis.
The aforementioned carbocyclic nucleosides and the pharmaceutically acceptable salts thereof, when administered to a patient, are capable of producing, directly or indirectly, anti-inflammatory compounds. Such a compound may be produced by hydrolysis or it may be a metabolite. These compounds are, therefore, useful in the treatment of psoriasis and other inflammatory skin diseases. There is currently great interest in finding new therapies for the foregoing diseases.
In one embodiment, the present invention relates to compounds, pharmaceutical compositions and methods for the treatment of psoriasis. Psoriasis is a chronic, autoimmune disease that appears on the skin. In psoriasis, the growth cycle of skin cells is accelerated by faulty immune signals, but the exact cause of the disease is not known. The research studies in this area suggest that increased proliferation and hyperplasia of the epidermal cells are implicated in the pathogenesis of psoriasis [Anderson et. al., Pathogenesis of skin disease, 67 (1986)]. Psoriasis is also considered to be an inflammatory skin disease in which neutrophils are associated with psoriatic lesions. Also, higher levels of arachidonic acid in the psoriatic plaques than in normal tissues are also reported in the literature. The metabolites of arachidonic acid play an important role in psoriasis because they are vasodilators and chemoattractants for neutrophils. It is also known that in the psoriatic lesions, Psoriasis Susceptibility-related RNA Gene Induced by Stress (PRINS), 12R-lipoxygenase and IL-20 activities are increased significantly. The enhanced proliferation of keratinocytes in the psoriatic plaques is also documented in the literature. It has been found that in psoriatic lesions, cyclic adenosine monophosphate (cAMP) levels are decreased, which may be result in diminished regulation of cell division due to less activation of the protein kinase. These studies further suggest that psoriasis is not merely a disease of the epidermis [Farber et. Al., Psoriasis: a disease of the total skin. J. Am. Acad. Dermat. 12, 150 (1985); Powrie et. al. J. Cxp. Med. 179, 589 (1994)].
Psoriasis is a prevalent disease, and it has been estimated that approximately 3% of the population of the world is suffering from psoriasis. This includes 2.2% of the population of the United States of America alone. It is a worthwhile goal to develop novel drugs for the treatment of this chronic disease. A wide variety of non-specific drugs such as lithium, β-blockers, antimalarials, corticosteroids and nonsteroidal anti-inflammatory agents have been investigated for the control of psoriasis [Abel et. al., J. Am. Acad. Dermatol. 15, 1007 (1986)], however, there are no specific drugs in the market for this disease.
The compounds currently commercially available for the treatment of psoriasis suffer from one or more deficiencies, including side effects, lack of sufficient efficacy and an inconvenient or non-esthetic method of administration. Accordingly, the search for effective treatments continues. The present invention relates to new and effective compounds for the treatment of psoriasis and other inflammatory skin diseases.
Animal models for the evaluation of the efficacy of drug molecules for the treatment of psoriasis are well established [Schon et. al., Nature Med. 3, 183-188 (1997); Wrone-Smith et. al., J. Clin. Invest. 98, 1878-1887 (1996); Christofidou-Solomidou et. al., J. Am. Pathol. 150, 631-639 (1997); Nickoloff et. al., J. Invest. Dermatol. 108, 539 (1997); Prens et. al. Clin. Dermatol. 13, 115-129 (1995); Carroll et. al., Cell 83, 957-968 (1995); Sundberg et. al., Handbook of Mouse Mutations with Skin and Hair Abnormalities, 253-268 (1994); Boehncke et. al., Arch. Dermatol. Res. 286, 325-330 (1994) and Boehncke et. al., Nature 379, 777 (1996)].
Abacavir, (−) cis-[4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-yl]-1-methanol, a carbocyclic nucleoside which possesses a 2,3-dehydrocyclopentene ring, is referred to in U.S. Pat. No. 5,034,394 as a reverse transcriptase inhibitor. Recently, a general synthetic strategy for the preparation of this type of compound and intermediates was reported [Crimmins, et. al., J. Org. Chem., 61, 4192-4193 (1996) and 65, 8499-8509-4193 (2000)]. As discussed in greater detail below, in a particular embodiment, the present invention relates to novel esters of abacavir, including, but not limited to (−) cis-[4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-hydroxymethyl acetate (also referred to herein as Prurisol) and the pharmaceutically acceptable salts thereof. Prurisol is an orally bioavailable compound for the treatment of inflammatory skin diseases such as psoriasis, eczema and seborrhiasis.